ABSTRACT
The gut microbiota affects nutrient acquisition and energy regulation of the host, and can influence the development of obesity, insulin resistance, and diabetes. During feeding, gut microbes produce short-chain fatty acids, which are important energy sources for the host. Here we show that the short-chain fatty acid receptor GPR43 links the metabolic activity of the gut microbiota with host body energy homoeostasis. We demonstrate that GPR43-deficient mice are obese on a normal diet, whereas mice overexpressing GPR43 specifically in adipose tissue remain lean even when fed a high-fat diet. Raised under germ-free conditions or after treatment with antibiotics, both types of mice have a normal phenotype. We further show that short-chain fatty acid-mediated activation of GPR43 suppresses insulin signalling in adipocytes, which inhibits fat accumulation in adipose tissue and promotes the metabolism of unincorporated lipids and glucose in other tissues. These findings establish GPR43 as a sensor for excessive dietary energy, thereby controlling body energy utilization while maintaining metabolic homoeostasis.
Subject(s)
Fatty Acids, Volatile/metabolism , Gastrointestinal Tract/microbiology , Insulin/metabolism , Lipid Metabolism , Microbiota , Receptors, G-Protein-Coupled/metabolism , Adipose Tissue, White/metabolism , Animals , Energy Metabolism , GTP-Binding Protein alpha Subunits, Gi-Go/metabolism , GTP-Binding Protein beta Subunits/metabolism , GTP-Binding Protein gamma Subunits/metabolism , Liver/metabolism , Liver/pathology , Male , Mice , Mice, Knockout , Models, Biological , Muscles/metabolism , Muscles/pathology , Obesity/metabolism , Obesity/pathology , Organ Specificity , PTEN Phosphohydrolase/metabolism , Protein Kinase C/metabolism , Receptors, G-Protein-Coupled/deficiency , Signal Transduction , Thinness/metabolism , Thinness/pathology , Type C Phospholipases/metabolismABSTRACT
An animal model for the early detection of common fatal diseases such as ischemic diseases and cancer is desirable for the development of new drugs and treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in a number of diseases, including cancer. Here, we established transgenic (Tg) mice that carry HRE/ODD-luciferase (HOL) gene, which generates bioluminescence in an HIF-1-dependent manner and was successfully used in this study to monitor HIF-1 activity in ischemic tissues. To monitor carcinogenesis in vivo, we mated HOL mice with rasH2 Tg mice, which are highly sensitive to carcinogens and are used for short-term carcinogenicity assessments. After rasH2-HOL Tg mice were treated with N-methyl-N-nitrosourea, bioluminescence was detected noninvasively as early as 9 weeks in tissues that contained papillomas and malignant lesions. These results suggest that the Tg mouse lines we established hold significant potential for monitoring the early onset of both ischemia and carcinogenesis and that these lines will be useful for screening chemicals for carcinogenic potential.
Subject(s)
Carcinogenicity Tests/methods , Hypoxia-Inducible Factor 1/metabolism , Ischemia/diagnosis , Luminescent Proteins/metabolism , Neoplasms, Experimental/diagnosis , Papilloma/diagnosis , Alkylating Agents/toxicity , Animals , Blotting, Southern , Female , Genes, ras , Humans , Image Processing, Computer-Assisted , Ischemia/chemically induced , Ischemia/metabolism , Luminescent Measurements , Male , Methylnitrosourea/toxicity , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Neoplasms, Experimental/chemically induced , Neoplasms, Experimental/metabolism , Papilloma/chemically induced , Papilloma/metabolism , RNA, Messenger/genetics , Real-Time Polymerase Chain ReactionABSTRACT
The angiotensin-converting enzyme (ACE) plays a crucial role in male fertilization and is a key regulator of blood pressure. Testicular ACE (tACE), the germinal specific isozyme expressed on different promoters, exclusively carries out the role of ACE in fertility, although the site and mode of action are not well known. To investigate the contribution of tACE in fertilization, we produced transgenic mouse lines carrying a dipeptidase-inactivated mutant. Although the transgenic mice showed normal blood pressure, kidney morphology, and fertility, reduced fertilization was observed after in vitro fertilization (IVF). The sperm-zona pellucida (ZP) binding was exclusively impaired in these lines in a manner similar to that observed in an Ace knockout mouse. The dipeptidase activity was reduced in epididymal ingredients but not in the testis. Furthermore, direct application of mutant protein did not suppress sperm-ZP binding of intact sperm during IVF, implying that the dipeptidase-inactivated mutant affects sperm modification in the epididymis for ZP binding. Our results indicate that the dipeptidase-inactivated tACE acts in vivo, suggesting that tACE contributes to fertilization as a dipeptidase at least in the epididymis.
